title: Heteromeric MT1/MT2 melatonin receptors modulate photoreceptor function.
abstract: The formation of G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) heteromers enables signaling diversification and holds great promise for improved drug selectivity. Most studies of these oligomerization events have been conducted in heterologous expression systems, and in vivo validation is lacking in most cases, thus questioning the physiological significance of GPCR heteromerization. The melatonin receptors MT1 and MT2 exist as homomers and heteromers when expressed in cultured cells. We showed that melatonin MT1/MT2 heteromers mediated the effect of melatonin on the light sensitivity of rod photoreceptors in mice. This effect of melatonin involved activation of the heteromer-specific phospholipase C and protein kinase C (PLC/PKC) pathway and was abolished in MT1(-/-) or MT2(-/-) mice, as well as in mice overexpressing a nonfunctional MT2 mutant that interfered with the formation of functional MT1/MT2 heteromers in photoreceptor cells. Not only does this study establish an essential role of melatonin receptor heteromers in retinal function, it also provides in vivo support for the physiological importance of GPCR heteromerization. Thus, the MT1/MT2 heteromer complex may provide a specific pharmacological target to improve photoreceptor function.
authors.affiliation: 1Neuroscience Institute and Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, GA 30310, USA.
authors.forename: Kenkichi
authors.initials: K
authors.lastname: Baba
authors.forename: Abla
authors.initials: A
authors.lastname: Benleulmi-Chaachoua
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Journé
authors.forename: Maud
authors.initials: M
authors.lastname: Kamal
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Guillaume
authors.forename: Sébastien
authors.initials: S
authors.lastname: Dussaud
authors.forename: Florence
authors.initials: F
authors.lastname: Gbahou
authors.forename: Katia
authors.initials: K
authors.lastname: Yettou
authors.forename: Cuimei
authors.initials: C
authors.lastname: Liu
authors.forename: Susana
authors.initials: S
authors.lastname: Contreras-Alcantara
authors.forename: Ralf
authors.initials: R
authors.lastname: Jockers
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tosini
mesh_terms: D000818:Animals; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D055503:Protein Multimerization / Q000502:physiology*; D044122:Receptor, Melatonin, MT1 / Q000235:genetics / Q000378:metabolism*; D044123:Receptor, Melatonin, MT2 / Q000235:genetics / Q000378:metabolism*; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology / Q000378:metabolism*; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism
chemical_list: D005136:Eye Proteins; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D010738:Type C Phospholipases